One-third of all individuals in the United States alone will develop cancer. Although the five year survival rate has risen dramatically nearly fifty percent as a result of progress in early diagnosis and therapy, cancer still remains second only to cardiac disease as a cause of death in the United States. Twenty percent of Americans die from cancer, half due to lung, breast, and colon-rectal cancer. Moreover, skin cancer remains a health hazard.
Designing effective treatments for patients with cancer has represented a major challenge. The current regimen of surgical resection, external beam radiation therapy, and/or systemic chemotherapy has been partially successful in some kinds of malignancies, but has not produced satisfactory results in others. One approach to treating cancer has been to induce apoptosis (cell death) of targeted tumor cells; therefore, mechanisms inducing apoptosis are of interest. One such mechanism has been reported where the Fas ligand, (FasL) (also known as CD95L and APO-IL), a cell surface molecule belonging to the tumor necrosis factor family, induces apoptosis of Fas-bearing tumor cells. Seino, et al., Nature Med., 3(2):165 (1997).
In another approach, cancer cell lines have been characterized. For example, it has been reported that all human melanoma lines tested in a number of studies express endothelin B-receptor (ETRB) (Yohn, et al., Biochem. Biophys. Res. Commun., 201:449-57 (1994); Kikuchi, et al., Biochem. Biophys. Res. Commun., 219:734-9 (1996); Ohtani, et al., Biochem. Biophys. Res. Commun., 234:526-30 (1997); Zhang, et al., Brit. J. Cancer, 78:1141-6 (1988)); moreover, expression is correlated with their differentiation state. Increased endothelin A-receptor (ETRA) expression is associated with induced differentiation of A375 melanoma cells, while they predominantly express ETRB in their malignant state (Ohtani, et al., Biochem. Biophys. Res. Commun., 234:526-30 (1997)). Unfortunately, the roles of endothelin receptors (ETRs) is not clear from previous studies. While one report indicates that endothelin-1 (ET1), acting through the ETRB, mediates mitogenic and chemokinetic effects on melanoma cells (Yohn, et al., Biochem. Biophys. Res. Commun., 201:449-57 (1994)), another report suggests other mechanisms for ET1 (Okazawa, et al., J. Biol. Chem., 273:12584-92 (1998)). Moreover, at least in one study, the focus of ETRB has been in regards to hypertension (Hashimoto, et al., Biol. Pharm. Bull., 21(8):800-804 (1998)). Additionally, endothelin-3 (ET3) has been reported on, however, many such reports are regarding developing non-malignant (normal) cells (Lahau, et al., PNAS, 93:3892-7 (1996)).
Studies have reported on ETRA and ET1 activity in regards to malignant cells, however, these studies were performed in vitro. For example, see, Nelson, et al., Cancer Res., 56:663-8 (1996).
Therefore, there remains a need to identify compounds which can be used in vivo to treat diseases such as cancer. In particular, there is a need to be able to selectively target malignant cells and induce cell death.
The present invention provides compositions and methods of treatment. In one aspect, a method of treating cancer is provided. In one embodiment, the method comprises administering to an individual in need of treatment for cancer, an inhibitor of an endothelin receptor activity, in a therapeutically effective amount. Preferably, the receptor is an endothelin B- or A-receptor. Administration can occur by a number of methods known in the art including by administration directly to the tumor site, or preferably, administration is systemic.
In one aspect, any kind of cancer is treated. Preferably, the cancer is skin, ovarian or prostrate cancer. In another preferred embodiment, the cancer is in a metastatic state.
In one embodiment, the inhibitor is an endothelin B-receptor or A-receptor antagonist. In a preferred embodiment, the inhibitor is BQ788 or a derivative thereof. In another preferred embodiment, the inhibitor is an antisense molecule to an endothelin receptor nucleic acid or an endothelin receptor agonist nucleic acid.
In another aspect, the invention provides a method for reducing abnormal proliferation or inducing differentiation of a cell. In a preferred embodiment, said cell comprises an endothelin receptor, preferably, an endothelin B-receptor. In one embodiment, the method comprising administering an inhibitor to an endothelin receptor to said cell in an amount for reducing proliferation or inducing differentiation. In yet another embodiment, a method for inducing apoptosis in a cell is provided. One method comprises administering an inhibitor to an endothelinreceptor, preferably an endothelin B-receptor, to said cell in an amount for inducing apoptosis. Preferably, the cell is a cancer cell.
Also provided herein is a method for screening for a bioactive agent capable of interfering with the binding of an endothelin receptor, preferably an endothelin B-receptor, and a ligand. In a preferred embodiment, the method comprises combining an endothelin receptor, a candidate bioactive agent and a ligand, and determining the binding of said receptor and said ligand. Preferably, the ligand is selected from the group consisting of endothelin 3, S6c, BQ-3020, and BQ-788,
In another aspect, a method for delivering a substance to a cancerous cell in an individual is provided. The method comprises conjugating a substance to BQ788 or a derivative thereof to form a conjugate and administering said conjugate to said individual.